Cabozantinib plus Nivolumab and Ipilimumab in Renal-Cell Carcinoma.

BACKGROUND: The efficacy and safety of treatment with cabozantinib in combination with nivolumab and ipilimumab in patients with previously untreated advanced renal-cell carcinoma are unknown. METHODS: In this phase 3, double-blind trial, we enrolled patients with advanced clear-cell renal-cell carcinoma who had not previously received treatment and had intermediate or poor prognostic risk according to the International Metastatic Renal-Cell Carcinoma Database Consortium categories. Patients were randomly assigned to receive 40 mg of cabozantinib daily in addition to nivolumab and ipilimumab (experimental group) or matched placebo in addition to nivolumab and ipilimumab (control group). Nivolumab (3 mg per kilogram of body weight) and ipilimumab (1 mg per kilogram) were administered once every 3 weeks for four cycles. Patients then received nivolumab maintenance therapy (480 mg once every 4 weeks) for up to 2 years. The primary end point was progression-free survival, as determined by blinded independent review according to Response Evaluation Criteria in Solid Tumors, version 1.1, and was assessed in the first 550 patients who had undergone randomization. The secondary end point was overall survival, assessed in all patients who had undergone randomization. RESULTS: Overall, 855 patients underwent randomization: 428 were assigned to the experimental group and 427 to the control group. Among the first 550 patients who had undergone randomization (276 in the experimental group and 274 in the control group), the probability of progression-free survival at 12 months was 0.57 in the experimental group and 0.49 in the control group (hazard ratio for disease progression or death, 0.73; 95% confidence interval, 0.57 to 0.94; P = 0.01); 43% of the patients in the experimental group and 36% in the control group had a response. Grade 3 or 4 adverse events occurred in 79% of the patients in the experimental group and in 56% in the control group. Follow-up for overall survival is ongoing. CONCLUSIONS: Among patients with previously untreated, advanced renal-cell carcinoma who had intermediate or poor prognostic risk, treatment with cabozantinib plus nivolumab and ipilimumab resulted in significantly longer progression-free survival than treatment with nivolumab and ipilimumab alone. Grade 3 or 4 adverse events were more common in the experimental group than in the control group. (Funded by Exelixis; COSMIC-313 ClinicalTrials.gov number, NCT03937219.).

Controversies on the treatment of ovarian cancer with dose-dense chemotherapy.

Epithelial ovarian cancer is the most lethal gynaecological malignancy with an estimated 295,414 new cases and 184,799 deaths around the world. Cytoreductive surgery and combination chemotherapy have remained a standard therapy for decades. The majority of women diagnosed with ovarian cancer will receive systemic chemotherapy for recurrent or advanced diseased. In recent years, therapies such as anti-angiogenics, PARP inhibitors, and dose-dense chemotherapy have emerged as novel strategies against ovarian cancer. Dose-dense chemotherapy, usually with a carboplatin and paclitaxel regimen, has been proposed as an alternative to conventional chemotherapy for these patients. However, the results for different trails are inconsistent and dose-dense chemotherapy remains controversial. Results from the JGOG 3016 study showed a progression free survival and overall survival benefit, with increased neurotoxicity and anaemia. While the GOG 262, MITO-7, GOG 252 and ICON8 studies found no benefit on progression free survival, with a recent meta-analysis concluding that three weekly chemotherapy remains the standard of care. Ovarian cancer molecular subtypes and differences in pharmacogenetics between populations may explain the differences in response to dose dense chemotherapy, however our understanding of this factors is still lacking. Here, we reviewed the evidence for and against dose-dense chemotherapy and the possible factors for the different results among trials.